Atazanavir: a suitable case for TDM?
Simon Collins, HIV i-Base
Numerous studies at this workshop explored the potential for indiviudalised dosing with atazanavir, relating to individual patient absorption, the use of ritonavir boosting ands interations with HIV and TB medications.
Atazanavir is widely used because it is generally well tolerated, has a low pill count and only requires once-daily dosing. Ritonavir boosting is routinely recommended to maximise drug exposure, and to reduce the risk of low trough levels and interpatient variability. However, higher atazanavir exposure is related to risk of hyperbilirubinaemia and the ritonavir boosting negatively impacts on lipid profiles.
As with efavirenz, the study from Columbo and collegues that identified genetic polymorphisms associated with absorption showed a higher rate of discontinuation of atazanavir due to side effects in patients with compared to those without these markers (52% vs. 20%, p=0.008). 
Taburet and colleagues reported results from a substudy (n=15) of the INDUMA trial where treatment naive patients were prescribed atazanavir/ritonavir (300mg/100mg QD) plus 2 nukes (not including tenofovir) and then randomised to continue on the same regimen or switch to unboosted atazanavir (400mg), maintaining the nukes. 
Atazanavir levels (adjusted geometric mean ratios) for Cmin and AUC dropped by 10% (5.8-19%) and 34% (26-46%) from the switch (week 0) and after 4 weeks on the reduced regimen. As expected, all PK parameters reduced without boosting and interpatient variability increased (see Table 1).
Table 1. Atazanavir levels: geometric mean (CV%) with and without ritonavir boosting
|week 0 ATZ/r 300/100||week 4 ATZ 400|
|Cmax (ng/mL)||3317 (39%)||1895 (69%)|
|Ctrough (ng/mL)||543 (92%)||64 (125%)|
|AUC 0-24 (ng*h/mL)||35617 (52%)||12197 (81%)|
However , despite the reduced atazanavir levels, 14/15 patients maintained viral suppression <50 copies/mL at 48 weeks, with only one patient experiencing a blip (to 113 copies/mL). Regazzi and colleagues presented results from using therapeutic drug monitoring in treatment-experienced patients using atazanavir, with and without ritonavir. 
The target range for atazanavir is 150-850 ng/mL.
The group analysed samples from 170 patients (with and without HCV coinfection) using various dosing regimens including ATZ/r 300/100 QD (n=79), ATZ 400 QD (n=57), ATZ 300 QD (n=11), ATZ/r 400/100 (n=5), ATZ 400 BID (n=8) and ATZ/r 200/100 QD (n=10). The main comparison between ATZ/r 300/100 QD and ATZ 400 QD showed lower atazanavir exposure and wider interpatient variability (CV%) without ritonavir (see Table 2).
Although both regimens showed similar levels of viral suppression (~84%), significant differences were seen between patients with or without HCV coinfection.
With the 400mg QD regimen, monoinfected patients experienced significantly lower trough levels (240 [100-400] vs. 600 [400-950] ng/mL, p<0.001). Conversely, coinfected patients using 400mg QD achieved similar trough levels to both mono- and coinfected patients using the 300/100mg dosing.
The authors do not comment on why this may be the case and it is unclear whether this was a real effect directly relating to coinfection or possible confounding with drug use or adherence (if IDUs were less adherent, they would tend to have lower trough levels).
Guillemi and colleagues from British Columbia looked at using TDM to indentify patients with high atazanavir trough levels (>900 ng/mL using ritonavir boosting) and then to confirm unboosted levels were >150 ng/mL prior using 400mg unboosted as a maintenance dose. 
They identified 20 patients (14 using tenofovir/FTC and 6 using abacavir/3TC) with baseline median [IQR] trough level of 1369 [1090-1620] ng/mL. Median trough level after 7-10 days on 400mg ATZ (unboosted) was 173 [96-301] ng/mL. CD4 was unchanged and no patient experienced viral rebound, although total bilirubin levels significantly declined (from 52 [28-64] to 18 [12-24] umol/L, p<0.001).
Table 2. Atazanavir exposure with and without ritonavir
|ATZ/r 300/100mg QD||ATZ 400mg QD|
|Ctrough ng/mL, mean [IQR] (CV%)||720 [430-1200] (79%)||340 [130-600] (147%)|
|% viral load <50 copies/mL||84.8 %||84.8 %|
The 9/20 patients with Ctrough <150 ng/mL (4 on abacavir, 5 on tenofovir) were switched back to the 300/100 boosting regimen while 11/20 continued on 400mg QD unboosted atazanavir.
A second study from the same group looking at the relationship between tenofovir use and unboosted atazanavir levels and showed that some patients maintained undetectable viral load despite trough level <150 ng/mL. 
The mdian atazanavir trough level in 43 patients was 242 (range 106-1100) ng/mL. Four patients with low trough levels (107-131 ng/mL) increased their dose to 600mg QD, resulting in trough increases to 222-294 ng/mL).
Of 31 patients with undetectable viral load at baseline, 30/31 remained <50 copies/mL.
Atazanavir and raltegravir
Two studies looking at the interaction between raltegravir and atazanavir suggest that individual monitoring is likely to be important when considering using these drugs in the same combination.
Molto and colleagues presented results from a study in 15 HIV-positive patients (4 women) who added raltegravir 800mg once-daily for 10 days, to the regimens of patients already using 400mg atazanavir once-daily for at least the previous two weeks. Use of tenofovir or proton pump inhibitors was not permitted. Both drugs were given with a light meal.
Previous studies have shown that atazanavir inhibits raltegravir metabolism by UGT1A1, boosting raltegravir exposure.
The geometric mean ration (95%CI) for Cmax and AUC 0-24 were compared with historical data on 20 HIV-negative individuals receiving raltegravir with a high fat meal.
Mean (IQR) raltegravir values for Cmax, Tmax, AUC0-24h and Ctrough were 5.36 (3.22-8.91 uM/mL, 2.95 (2.09-4.18) hours, 29.04 (20.46-41.22) uM*h/mL and 69.53 (39.58-122.16) nM/mL respectively. Raltegravir Ctough was <33nM in four patients.
Compared to historical controls using a single 400mg dose of raltegravir GMR (95%CI) for Cmax, AUC 0-24h and Ctrough were 2.81 (1.43-5.50) p=0.004; 1.18 (0.74-1.88) p=0.465 NS and 0.15 (0.07-0.32) p<0.001 respectively. The comparisons were not normalised for comparing the 400mg and 800mg dose, so the practical use of information about the almost 3-fold higher Cmax and 85% reduction in Ctrough are unclear. 
Ripamonti and colleagues presented what was perhaps a more pharmacologically useful study. This group switched 21 HIV-positive patients to twice-daily atazanavir (200mg without ritonavir-boosted) plus raltegravir (400mg twice-daily), due to either drug resistance or tolerability on their current regimen. 
PK results after at least 2 weeks on the new combinatin showed wide interpatient variability for parameters of both durgs. The geometric mean (95%CI) for atazanavir AUC0-12h, Cmax and Cmin were 6257 (4334-8172) ng*h/ML, 1062 ng/mL (676-1448) ng/mL and 227 (122-332) ng/mL respectively. The geometric mean (95%CI) for raltegravir AUC0-12h, Cmax and Cmin were 9085 (6317-11,854) ng*h/ML, 2402 ng/mL (1496-3308) ng/mL and 132 (1-263) ng/mL respectively. Five patients had atazanaivr levels below the minimum target of 150 ng/mL. About 60% of patients entered the study with undetectable viral load, which was achieved by all patients two weeks after the switch, though these results need to show durability before and comment can be made about efficacy of the combination.
Of concern, the investigators concluded that this combination ‘may’ provide adequate plasma concentrations for ‘some’ patients. Clearly the only reliable way to identify thos patinets is through using TDM on an individual basis.
Drug interaction studies with atazanavir and non-HV drugs included an antimalarial study (see article above). 
While ritonavir boosting clearly improves atazanavir levels, the results from these studies indicate that for some patients, when supported by TDM, there may be an option to maintain viral suppression on an unboosted regimen.
The wide interpatient variability appears to protect some patients even when druginteractions are known to reduce theraputic levels.
For other combinations, notably with raltegravir, and especially when using novel dosing, TDM seems essential.
Unless otherwise stated all references are to the Programme and Abstracts of the 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam.
1. Colombo S et al. Association of pharmacogenetic markers with premature discontinuation of first-line ART. Oral poster O-03.
2. Taburet A et al. Pharmacokinetics of atazanavir administered once daily with or without ritonavir in HIV infected patients: INDUMA Study. Poster abstract P-32.
3. Regazzi M et al. Therapeutic monitoring and variability of atazanavir in experienced HIV-infected patients receiving boosted or unboosted regimens. Poster abstract P-35.
4. Guillemi S et al. A short trial of unboosted atazanivir in patients receiving atazanavir/ritonavir with high trough levels to select candidates for unboosted atazanavir maintenance therapy. Poster abstract P-46.
5. Harris M et al. Atazanavir trough levels in patients receiving unboosted atazanavir and tenofovir. Poster abstract P-21.
6. Molto J et al, Pharmacokinetics and safety of once-daily raltegravir (800mg) plus atazanavir (400mg) in HIV-infected patients. Oral abstract O-13.
7. Ripamonti D et al. Steady-state pharmacokinetics of atazanavir (200mg BID) when combinaed with raltegravir (400mg BID) in HIV-infected adults. Oral abstract O-14.
8. Ref: Van Luin M et al. Drug interactions between atovaquone/proguanil and antiretroviral agents. Oral poster O-19.